The invention relates to methods of and apparatus for activating the muscle cells or nerves of the uterus or cervix. More particularly, the invention relates to a method and instrument useful for stimulating or inhibiting uterine contractility for producing cervical ripening at the end of the period of gestation; and for regulating the uterus or cervix in non-pregnant patients.
Preterm labor is one of the major pathological states most frequently complicating pregnancy. Preterm birth is the major cause of prenatal morbidity and mortality (75%) and long term neurological handicaps. In spite of the use of different new tocolytics, the incidence of preterm labor and the incidence of prenatal morbidity and mortality has not changed over the last decades.
U.S. Pat. No. 5,397,344 and U.S. Pat. No. 5,522,877, both of which are incorporated herein by reference, address diagnosing labor (term and preterm) which is a significant problem faced by obstetricians. Preterm labor is the pathological state most frequently associated with this dilemma. Moreover, term labor often requires adjuvant therapy to halt or augment labor. Since there is spontaneous uterine activity during pregnancy, it is often not possible to distinguish between physiological uterine activity or preterm labor. The state of the cervix is commonly used as a predictor of preterm birth. However, the softening of the cervix, as well as the appearance of uterine contractions are relatively late in preterm labor.
Antiprogestins induce preparatory changes in the uterus in all stages of pregnancy. This results in the increase in myometrial responsiveness to oxytocic stimuli such as oxytocin or prostaglandins. The major effect of antiprogestins on the uterus is the preparation or conditioning of the myometrium to labor and delivery by inducing intercellular coupling which manifests itself by an increase in propagation due to an increase in gap junctions.
The uterus is quiescent throughout pregnancy to maintain a tranquil environment for the growing fetus. At the end of pregnancy normally the uterus beings to contract forcefully in a phasic manner (labor) to expel the fetus and other products of conceptions. Abnormally the uterus sometimes either begins to contract and labor prior to term (preterm labor) or fails to contract at term. Preterm labor occurs in about 10% of all pregnancies whereas the incidence of insufficient or absence of contractions at term is also very high (3 to 13%). In most cases the clinician is faced with the decision to either inhibit labor or stimulate it depending on the circumstances. However, the clinician has only subjective methods (state of cervix or number of contractions but not force of contraction) on which to base a decision.
The uterus is now known to pass through a series of steps prior to and during labor to prepare the muscle to contract in a coordinated, synchronous and therefore forceful manner. These steps include the development of gap junctions (low electrical resistance contacts), receptors and other events between and on the muscle cells that allow the uterus to contract as a syncytium and react to contractile agents. Contractions of the uterus are dependent upon electrical activity, therefore the presence of gap junctions is an important component of this process. These steps are known to be regulated by various physiological signals (hormones) and can be controlled pharmacologically. When the muscle cells pass through this state they become electrically and metabolically coupled. This state allows the uterus to contract forcefully and frequently. Although this process is known to occur during pregnancy, it also appears during the menstrual cycle and may be present in various pathological conditions of the uterus such as dysmenorrhea, endometriosis, habitual abortion, allergic reactions, etc. However, at present, the obstetrician or gynecologist has no objective method to evaluate this process and to intervene when necessary by activating muscle cells or nerves of the uterus or cervix. The clinical judgement as to treatment is enhanced by procedures which define the state of the patients uterus such as the procedures of U.S. Pat. No. 5,522,877 and U.S. Pat. No. 5,397,344. There are, however, no current procedures for using the concepts of these patents to stimulate or inhibit activity in order to treat patients have the aforementioned difficulties.
Numerous studies show that gap junctions are present in almost all cells and their presence and function has been associated with normal physiological control. Gap junctions are also known to be altered either structurally or functionally in pathological states such as cancer, hypoxia, inflammation, etc. Many studies demonstrate that one can assess gap junction presence or function by electrical simulation and recording of electrical events in adjacent cells.
There have been a number of studies with respect to this matter such as Miller, S. M., et al., "Improved Propagation in Myometrium Associated with Gap Junctions During Parturition", American Journal of Physiology, pages 130-141 (1989), incorporated herein by reference, in which gap junction measurements were made on uterine tissue of pregnant rats. Additional studies which are reported in the literature include: Garfield et al., "Modulation of Myometrial Gap Junctions: Toxicological Implications", In Vitro Toxicology, A Journal of Molecular and Cellular Toxicology, Vol. 3, Number 1, pp. 41-59 (1990); Chwalisz et al., "The Progesterone Antagonist Onapristone Increases the Effectiveness of Oxytocin to Produce Delivery without Changing the Myometrial Oxytocin Receptor Concentrations", Am. J. Obstet. Gynecol, Vol. 165, No. 6, Part l, pp. 1760-1770 (December 1991); Garfield, "Structural and Functional Studies of the Control of Myometrial Contractility and Labor", The Onset of Labor: Cellular & Integrative Mechanisms, pp. 55-79 (1988); Garfield et al., "Effects of the Antiprogesterone RU 486 on Preterm Birth in the Rate", American Journal of Obstetrics and Gynecology, Vol. 157, No. 5, pp. 1281-1285 (November 1987); Demanczuk et al., "Myometrial Electrophysiologic Activity and Gap Junctions in the Pregnant Rabbit", American Journal of Obstetrics and Gynecology, Vol. 149, No. 5, pp. 485-491 (Jul. 1, 1984); Garfield, "Control of Myometrial Function in Preterm Versus Term Labor", Clinical Obstetrics and Gynecology, Vol. 27, No. 3, pp. 572-591 (September 1984); Puri et al., "Changes in Hormone Levels and Gap Junctions in the Rat Uterus During Pregnancy and Parturition", Biology of Reproduction, 27, 967-975 (1892); Garfield et al., "Endocrine, Structural, and Functional Changes in the Uterus During Premature Labor", American Journal of Obstetrics and Gynecology, Vol. 142, No. 1, pp. 21-27 (Jan. 1, 1982); Garfield et al., "Appearance of Gap Junctions in the Myometrium of Women During Labor", American Journal of Obstetrics and Gynecology, Vol. 140, No. 3, pp. 254-260 (Jun. 1, 1981); Garfield et al., "Presence of Gap Junctions in the Myometrium of Women During Various Stages of Menstruation", American Journal of Obstetrics and Gynecology, Vol. 138, No. 5, pp. 569-574 (Nov. 1, 1980); and Garfield et al., "Art Gap Junctions Necessary for Cell-to-Cell Coupling of Smooth Muscle?: An Update", Can. J. Physiol. Pharmacol., Vol. 70, pp. 481-490 (1992); each of which is incorporated herein by reference. While these studies each recognize various aspects of the phenomenon of interest, they do not suggest just how one would utilize the phenomenon in practical medical procedure to electrically stimulate or inhibit activity of the uterus or cervix.
The status (function, location, Identification, etc.) of nerves and their terminals in tissues can be quantified also by selectively stimulating the nerves with electrical parameters that do not affect surrounding tissues. This so-called "field stimulation" has been used in many studies to activate nerves or their varicosities in tissues to assess, localize and identify nerves in tissues. Exemplary of such studies are the following articles: Garfield et al., "A Functional and Structural Study of the Innervation of the Human Uterus", American Journal of Obstetrics and Gynecology, Vol. 160, No. 1, pp. 218-228 (January 1989); Bulat et al., "Studies of the Innervation of Rabbit Myometrium and Cervix", Can. J. Physiol. Pharmacol., Vol. 67, pp. 837844 (1989); and Buchanan et al., "Innervation and Gap Junction Formation in the Myometrium of Pregnant Little Brown Bats, Myotis lucifugus", The Anatomical Record, 221:611-618 (1988), each of which is incorporated herein by reference.
Prior methods and instruments for evaluating the status of the uterus have used external monitors which give little information of quantitative nature necessary to define the processes described above or to electrically stimulate or inhibit activity of the uterus or cervix.